Project Summary/Abstract As unprecedented numbers of people are living well into advanced decades of life, age-related diseases and conditions are a growing public health challenge. Telomere shortening is a molecular mechanism of aging that occurs because the machinery of DNA replication cannot fully copy to DNA ends on the lagging strand. Each successive cell division erodes telomere sequence. To counter this erosion, cells with self-renewal potential use a specialized polymerase called telomerase to lengthen telomeres. However, somatic cells do not express telomerase, and therefore experience continuous telomere shortening with increasing age. Eventually, critically short telomeres trigger cellular senescence and telomeric dysfunction. In aging tissues, cellular senescence leads to the decline of organ function and reduced stress response; both are commonly recognized symptoms of aging. In addition, short telomeres drive the pathogenesis of diverse conditions such as idiopathic pulmonary fibrosis, bone marrow failure, and dyskeratosis congenita. Very few strategies exist to address the problem of telomere shortening in aging and disease. We recently discovered that mice lacking Poly(ADP)Ribose Polymerase 3 (Parp3) have longer telomeres in multiple somatic cell types. The broad, long-term objectives of this proposal are to elucidate the mechanisms by which PARP3 suppresses telomere elongation and investigate the possibility that PARP3 is a tractable target to elongate telomeres in aging and diseased tissues. PARP3 is a catalytically active enzyme that attaches monomers of ADP(ribose) onto target proteins. In our preliminary data, specific PARP3 inhibition led to elongated telomeres. Therefore, PARP3 inhibitors are promising compounds to elongate telomeres in aging tissues. In addition, we observe that telomeres in PARP3-/- cells exhibit alterations in telomeric chromatin structure, suggesting a mechanistic basis for telomere elongation. Therefore, Specific Aim 1 will define the contribution of Parp3 to telomere length homeostasis. A thorough understanding of the role of Parp3 in telomere elongation is necessary for designing clinical strategies. Specific Aim 2 will determine whether PARP3 inhibition mitigates phenotypes of age-related decline on an organismal level using a mouse model of aging. Both aims will also test whether findings can be generalized from mouse to human cells. These studies will help us achieve a better understanding of the basic biology of aging and to develop interventional strategies that mitigate pathologies related to telomere shortening. The applicant Dr. Tovah Day has outlined a five-year career development plan to meet her goal of becoming an independent investigator focused on telomere and aging biology. Dr. Day has assembled an Advisory Committee of internationally recognized experts to provide scientific and career mentorship. Dana- Farber Cancer Institute is the ideal environment for completion of her scientific and career goals, given its outstanding research community and substantial record for training independent scientists.